ABSTRACT Atrial fibrillation (AF) is the most common sustained arrhythmia, currently affecting >33.5 million adults world- wide, with the highest rates in North America. Chronic kidney disease (CKD) is also highly prevalent and affects 14% of the U.S. and North American population. The burden of AF is 3-fold higher in CKD and affects up to 25% of CKD patients. AF is linked to poor outcomes. Our data demonstrate that among patients with CKD, incident AF is associated with a 3-to-7-fold greater risk of heart failure (HF), acute coronary syndromes (ACS), stroke, death and progression to end-stage renal disease (ESRD) vs. CKD patients without AF. Despite the high risks associated with AF, it is unknown whether AF therapies improve outcomes in the setting of CKD. The unique pathophysiology of AF in CKD, the effects of decreased renal clearance, as well as competing risks of non-AF related death may alter the effectiveness and safety of commonly used AF medications and procedures in CKD. To our knowledge, no published studies have evaluated the collective influence of AF therapies on kidney and cardiovascular outcomes in CKD. Trials of AF therapies have largely excluded patients with CKD. Prior observational studies have several notable limitations: (1) focus only on warfarin and not a comprehensive evaluation of other AF therapies; (2) focus only on stroke and death as outcomes; and (3) inadequate consideration of interim clinical measures that may affect receipt and outcomes of AF therapies. Our overall goal is to use real-world contemporary data to evaluate the risks vs. benefits of various AF therapies, including medications and procedures, in adults with CKD. We will perform a comparative effectiveness analysis to delineate whether treatment of AF impacts important kidney and cardiovascular outcomes in patients with vs. without CKD. To conduct these aims, we will use the Cardiovascular Research Network (CVRN) platform to study a community-based network of ~267,000 patients with AF from two participating health care systems in California; and we will externally validate these findings in a community- based cohort of ~392,000 patients in Ontario, Canada. We will evaluate the use, response and safety of current AF therapies (including anticoagulation, rate control agents, anti-arrhythmic agents and AF-related procedures) in patients with vs. without CKD. We will perform a comparative effectiveness analysis to delineate whether treatment of AF impacts important kidney and cardiovascular outcomes in patients with vs. without CKD. The data from this study may provide guidance for an integrated AF management approach to improve clinical outcomes in CKD and inform the design of future trials of patients with AF and CKD.